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to be more frequent in obese girls (
Castellano et al., 2011
). Moreover, alter-
ations of the reproductive axis in adulthood have also been observed in con-
ditions of persistent overweight; for example, hypogonadism of central
origin has been described in obese men (
Tajar et al., 2010
). As a whole, these
observations stress the close connection between the metabolic status and
reproductive function, including puberty onset.
Compelling evidence gathered in the last two decades has documented
the essential roles of the adipose hormone, leptin, in the metabolic control
of puberty and fertility (
Fernandez-Fernandez et al., 2006; Tena-Sempere,
2007
). The circulating levels of leptin are proportional to the amount of
body energy (fat) stores, so that leptin operates as signal of energy abundance
for the reproductive system. However, despite active research in this area,
the precise mechanisms and circuits whereby leptin conducts such biological
function are yet to be completely elucidated. In any event, it has now been
well demonstrated that leptin likely acts as a permissive (rather than trigger)
factor that allows puberty to proceed only if sufficient body energy reserves
are achieved (
Castellano et al., 2009; Roa et al., 2010
). The mechanisms for
this permissive action are probably multifaceted, as illustrated by the capacity
of leptin to operate at the different levels of the HPG axis (
Tena-Sempere,
2007
). Nonetheless, it is clear that the major site for the permissive effects of
leptin is the hypothalamus, where the adipose hormone is able to modulate
the GnRH neuronal system (
Cunningham, Clifton, & Steiner, 1999
). Yet,
this action seems to be conducted in an indirect manner, as GnRH neurons
do not physiologically express functional leptin receptors, as documented by
expression studies in rodents and primates (
Finn et al., 1998; Hakansson,
Brown, Ghilardi, Skoda, &Meister, 1998
), as well as by functional genomic
analyses that showed that selective elimination of leptin receptors in GnRH
neurons did not prevent puberty or fertility (
Quennell et al., 2009
).
Because of the indirect mode of leptin action on GnRH neurons,
research efforts have been devoted to elucidate the neuronal circuit whereby
leptin, and eventually other key metabolic signals, may transmit their regu-
latory actions to GnRH neurons. One pathway that has attracted consider-
able attention is that of Kiss1 neurons, whose role in the metabolic control of
reproduction in general, and of puberty onset in particular, has been exten-
sively analyzed. In this context, compelling evidence accumulated in recent
years has demonstrated that Kiss1 neurons in the hypothalamus may sense
different forms of metabolic stress and thus may convey the regulatory
actions of metabolic cues to the centers that control puberty (
Castellano
et al., 2009; Tena-Sempere, 2010
). The sensitivity of the hypothalamic Kiss1
